Reagent and method for providing coatings on surfaces

ABSTRACT

A grafting reagent and related method of using the reagent to form a polymeric layer on a support surface, and particularly a porous support surface, in a manner that provides and/or preserves desired properties (such as porosity) of the surface. The reagent and method can be used to provide a thin, conformable, uniform, uncrosslinked coating having desired properties onto the surface of a preformed, and particularly a porous, polymeric substrate. The method includes the steps of a) providing a porous support surface, b) providing a nonpolymeric grafting reagent comprising a photoinitator group, c) providing one or more polymerizable monomers adapted to be contacted with the surface, in the presence of the grafting reagent, and to be polymerized upon activation of the photoinitiator; and d) applying the grafting reagent and monomer(s) to the surface in a manner, and under conditions, suitable to coat the surface with the grafting reagent and to cause the polymerization of monomers to the surface upon activation of the grafting reagent.

This application is a divisional of U.S. application Ser. No.10/028,518, the entire disclosure of which is incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to chemical and/or physical modificationof the surface properties of industrially and medically importantsubstrates. In one such aspect, the invention relates to themodification of the surfaces of materials having small pores orapertures, such as distal protection devices for use in blood filtering.In a related aspect, the present invention relates to the modificationof surface properties for such purposes as providing surfaces withdesired characteristics, such as hydrophilicity and lubricity. In aparticular aspect, the invention relates to such surface modificationtechniques as chemical derivatization and photoinitiated polymerization.

BACKGROUND OF THE INVENTION

The chemical modification of surfaces to achieve desired chemical and/orphysical characteristics has been previously described. Often, thevarious coatings and techniques referred to above are used to coat thesurfaces of materials (e.g., medical devices) intended for temporary orpermanent placement in the body. In turn, the resulting coatingstypically provide a desired function or feature, such as lubricity, andmust do so in a manner that provides the desired combination of suchother properties as hemocompatability, durability, and sterility.

A number of patents generally relate to surface modification by the useof latent reactive groups to achieve covalent coupling of agents such asbiomolecules and synthetic polymers to various substrates. See, forexample, Applicant's U.S. Pat. Nos. 4,722,906, 4,826,759, 4,973,493,4,979,959, 5,002,582, 5,073,484, 5,217,492, 5,258,041, 5,263,992,5,414,075, 5,512,329, 5,512,474, 5,563,056, 5,637,460, 5,714,360,5,741,551, 5,744,515, 5,783,502, 5,858,653, 5,942,555, 6,007,833,6,020,147, 6,077,698, 6,090,995, 6,121,027, 6,156,345, 6,214,901 andpublished PCT Application Nos. US82/06148, US87/01018, US87/02675,US88/04487, US88/04491, US89/02914, US90/05028, US90/06554, US93/01248,US93/10523, US94/12659, US96/07695, US96/08797, US96/17645, US97/05344,US98/16605, US98/20140, US99/03862, US99/05244, US99/05245, US99/08310,US99/12533, US99/21247, US00/00535, US00/01944, US00/33643, andUS01/40255, (each of which is commonly owned by the assignee of theinvention described herein, and the disclosure of each is incorporatedherein by reference). The preferred latent reactive group is oftendescribed as a photochemically reactive functional group (“photoreactivegroup”). When exposed to an appropriate energy source, a latent reactive(e.g., photoreactive) group undergoes a transformation from an inactivestate (i.e., ground state) to a reactive intermediate capable of formingcovalent bonds with appropriate materials.

Such latent reactive groups can be used, for instance, to firstderivatize a target molecule (e.g., thermochemically), in order to thenphotochemically attach the derivatized target molecule to a surface.Such a sequential approach is suitable in many situations, but can lacksuch attributes as speed, versatility, and ease of use, particularlywhen used with target molecules that are inherently difficult to firstderivative, or need to be used under conditions that would result inloss of desirable (e.g., biological) activity.

In another approach, the surface itself can be provided (e.g.,derivatized or “primed”) with latent reactive groups, which can then beactivated while target molecules are in sufficient proximity to becomethus attached to the surface. For instance, Applicant's U.S. Pat. No.5,414,075, describes the use of linking agents to prime a surface toprovide the surface with photoactivatable groups. This patent describesa restrained, multifunctional reagent useful for priming a supportsurface, or for simultaneous application with a target molecule to asupport.

By contrast, there appear to be relatively few examples of surfacecoatings that are provided by the formation of polymers in situ upon thesurface, e.g., by grafting. For instance, Tazuke et al. discuss themodification of polymer surfaces by the use of a grafting technique thatinvolves treating a base polymer (e.g., polypropylene) with a reactingsolution that contains sensitizers (e.g., benzophenone) and a selectedpolymer to be grafted onto the base polymer. “A Novel Modification ofPolymer Surfaces by Photografting,” Tazuke et al., pp. 217-241, inModification of Polymers, ACS Symposium Series 121 American ChemicalSociety, 1980. The use of polymeric photosensitizers for initiatingpolymerization has also been described. See, for instance, “RadicalPolymerization,” C. H. Bamford, pp. 940-957 in Kroschwitz, ed., ConciseEncyclopedia of Polymer Science and Engineering, 1990.

Moreover, Applicant's own U.S. Pat. No. 5,741,551 describes the mannerin which molecules of reactive chemical unit can be bonded to a surface,via the activation of latent reactive groups. In turn, a differentmonomer, oligomer or polymer can be covalently bound to the reactivechemical unit, and in turn, to the support surface, for instance, bymeans of a polymerization reaction between the two.

In a related manner, Applicant's U.S. Pat. No. 5,714,360 describes achemical linking agent comprising a di- or higher functionalphotoactivatable charged compound. The linking agent has increasedhydrophilic character, as compared to the reagents of the '075 patentabove. Applicant's co-pending International PCT application No.PCT/US99/21247 further provides a method for the use of reagents of thetype described in the '360 patent as coating agents for forming apolymeric layer on a surface by graft polymerization. In its Backgroundsection, the co-pending PCT application describes common methods ofattaching a polymer to a support surface, including the attachment of apreformed polymer to a surface, and grafting a polymer to a surface.

PCT Publication No. WO 99/15917 (Baron, Novartis AG) describes a methodfor treating the surfaces of siloxane-containing hydrogel contactlenses. The publication describes the manner in which preformed polymersare grafted onto a surface using photogroups (such as benzophenone) asphotosensitizers. In a first treatment, the surface is functionalized bydipping it in a solvent solution containing the photosensitizer.Thereafter, the functionalized surface is contacted with a solutioncontaining macromer, which is grafted to the surface upon theapplication of UV light.

PCT Publication No. WO 01/17575 (STS Biopolymers, Inc.) describes amethod for graft polymerization of substrate surfaces. The publicationdescribes a method of coating a substrate, involving exposing asubstrate to an initiator capable of initiating a graft polymerizationreaction on the substrate, to generate reactive radical sites on thesurface of the substrate; contacting the substrate with a compositioncomprising one or more monomers in a medium which has differenthydrophilicity compared to the substrate, and grafting monomer moleculesonto the substrate by forming covalent bonds between monomer moleculesand the substrate at reactive radical sites on the substrate surface.

See also Anders et al., U.S. Pat. No. 6,096,369, which describes aprocess for making the surface of polymeric substrates hydrophilic. Theprocess includes coating the surface with a solution of a“macroinitiator,” after which a hydrophilic vinyl monomer solution isthen applied and the system activated in order to provide the freeradical polymerization of the monomers to the surface.

On a separate subject, a variety of approaches have been described foruse in providing coatings upon porous substrates. For instance,Applicant's U.S. Pat. No. 5,744,515 describes the manner in which porousmaterials such as vascular grafts can be coated with adhesion moleculesin order to promote capillary endothelialization once positioned invivo. In one embodiment, the adhesion molecules themselves bearphotoreactive groups, in order to permit the molecules to be contactedwith the surface and immobilized upon activation of the photoreactivegroups.

A relatively new type of medical device is referred to as a “distalprotection device,” for use in filtering blood in situ, downstream fromthe site at which an interventional procedure is being performed.Examples of such devices are described, for instance, in U.S. Pat. No.6,245,089. However, no teachings appear to exist in the art regardingeither the ability or desirability of providing polymeric coatings onsuch devices, particularly in a manner that does not substantially altertheir desired performance characteristics.

Indeed, Applicant has found that the above-described approaches andreagents, whether for attaching derivatized polymers, or for graftingpolymers onto surfaces, tend to be of considerably less utility forsurfaces having particularly small pores, interstitial spaces orapertures that are intended to remain open and unclogged in the courseof their intended use. Such pores and the like can tend to be clogged,particularly by the use of relatively hydrophilic coating agents, whichtend to “web” over the apertures, thereby jeopardizing the uniformityand/or utility of the thus-coated article.

To the best of Applicant's knowledge, the art does not teach, nor arethere commercial products that involve, the preparation or use ofnonpolymeric coating agents that are themselves attached to the poroussurface of an article in order to initiate photopolymerization from thesurface. Moreover, there remains a need for coating agents that can beused to coat relatively hydrophobic surfaces, and particularly for thosesurfaces that provide relatively small pores, interstitial spaces, orapertures.

BRIEF DESCRIPTION OF THE DRAWING

In the Drawing:

FIG. 1 shows a schematic diagram of a device for performing frictionmeasurements by the vertical pinch method described herein.

SUMMARY OF INVENTION

The present invention provides a grafting reagent and related method ofusing the reagent to form a polymeric coating on a support surface, andpreferably a porous support surface, in a manner that substantiallypreserves and/or provides desired properties to the surface, e.g.,preserves the desired porosity of the surface. In another aspect, theinvention provides a method of priming a support surface with thegrafting reagent itself, in a manner adapted to permit the formation ofa polymer coating by grafting. The invention also provides a poroussurface provided with a grafted polymer coating formed by such a method.Further, the invention provides a grafting system that includes agrafting reagent and polymerizable compounds as described herein.

The reagent and method are particularly useful for forming a thin,conformable, uniform, uncrosslinked coating having desired properties(e.g., a desired combination of such properties as lubricity,hemocompatability, thickness, and wettability) onto the surface of apreformed, and particularly a porous, polymeric substrate. The word“porous,” when used in this regard, will be used to generally refer topores, interstitial spaces, or other apertures or voids of a size and/orconfiguration that would be substantially occluded (e.g., by webbing)when coated with preformed polymers of a type formed in situ by thegrafting method described herein. By “substantially occluded,” in thisregard, it is meant that the pores would be affected (e.g., filled orconstricted) to an extent that would render the surface no longersuitable for its intended use.

In one aspect, the present invention provides a method of forming apolymeric coating on a support surface, the method comprising:

a) providing a support surface, preferably a porous support surface;

b) providing a nonpolymeric grafting reagent comprising at least onephotoinitator group, and preferably further comprising one or morelatent reactive (e.g., photoreactive) groups adapted to be activated inorder covalently attach the grafting reagent to the surface itself;

c) providing at least one polymerizable monomer solution adapted to becontacted with the surface, in the presence of the grafting reagent, andto be polymerized upon activation of the photoinitiator; and

d) applying the grafting reagent and monomer solution to the surface ina manner, and under conditions, suitable to coat the surface with thegrafting reagent and to cause the polymerization of monomers to thesurface upon activation of the grafting reagent, and optionally, toattach the grafting reagent to the surface upon activation of the latentreactive (e.g., photoreactive) group(s).

The moieties used to provide the photoinitiator and latent reactive(e.g., photoreactive) groups can be the same or different. For instance,in a preferred embodiment, the reagent includes a plurality of arylketone groups, each of which are adapted to serve either function. Insuch an embodiment, the actual use of any particular group (i.e.,whether it will serve as a photoinitiator or photoreactive group) isdetermined at the time and under the conditions of use. In alternativeembodiments, groups such as carbenes and nitrenes can serve as thephotoreactive group of a reagent, but are not adapted to photoinitiatemonomers of the type described herein. In such an alternativeembodiment, at least one photoinitiator group is therefore included aswell.

The method according to the present invention provides improved controlof the coating process (e.g., as compared to coating preformed polymers)and reduces or avoids many of the deficiencies of previous methods,particularly for use with surfaces providing small pore sizes (e.g.,“microporous” surfaces). The present invention provides for theconcentration of latent reactive (e.g., photoreactive) andphotoinitiating groups directly on the surface of a device thusmaximizing the efficiency of these groups and promoting the formation oflinear polymer chains (e.g. as compared to a crosslinked matrix whichresults from the use of preformed latent reactive (e.g., photoreactive)polymers).

The resultant polymeric coating can be selected and adapted so as toprovide the surface with desirable features in the course of itsmanufacture or use, or once positioned in vivo and/or used ex vivo,including permeability, antithrombogenicity, lubricity,hemocompatibility, wettability/hydrophilicity, durability of attachmentto the surface, biocompatibility, and reduced bacterial adhesion.

In a particularly preferred embodiment, the method and composition areused to coat the surfaces of devices such as emboli catching (also knownas “distal protection”) devices, of the type described in U.S. Pat. No.6,245,089, the disclosure of which is incorporated herein by reference.The composition provides particular advantages by being able to suitablycoat the surfaces of the porous materials, and thereby alter theirphysico-chemical features in a desired, controllable fashion, while notunduly clogging the pores in a manner that would render them unsuitablefor their intended purpose.

Various steps of the present method can be performed in any suitablemanner and order, preferably sequentially. These include theillumination step to attach the grafting reagent to the surface, as wellas the step of providing the polymerizable monomers, and the step ofilluminating the grafting reagent to initiate polymerization.

DETAILED DESCRIPTION

Support surfaces useful in the method of this invention provide anoptimal combination of such physical and mechanical properties asporosity, hydrophobicity/hydrophilicity, strength, flexibility,permeability, elongation, abrasion resistance, and tear resistance.

Examples of materials used to provide suitable support surfaces includepolyolefins, polystyrenes, poly(alkyl)methacrylates andpoly(alkyl)acrylates, polyacrylonitriles, poly(vinylacetates),poly(vinyl alcohols), chlorine-containing polymers such as poly(vinyl)chloride, polyoxymethylenes, polycarbonates, polyamides, polyimides,polyurethanes, polyvinylidene difluoride (PVDF), phenolics, amino-epoxyresins, polyesters, silicones, polyethylene terephthalates (PET),polyglycolic acids (PGA), poly-(p-phenyleneterephthalamides),polyphosphazenes, polypropylenes, parylenes, silanes, and siliconeelastomers, as well as copolymers and combinations thereof, as well ascellulose-based plastics, and rubber-like plastics. See generally,“Plastics,” pp. 462-464, in Concise Encyclopedia of Polymer Science andEngineering, Kroschwitz, ed., John Wiley and Sons, 1990, the disclosureof which is incorporated herein by reference. Parylene is the genericname for members of a unique polymer (poly-p-xylylene) series, severalof which are available commercially (e.g., in the form of “Parylene C”,“Parylene D” and Parylene N”, from Union Carbide). For example,“Parylene C”, is a poly-para-xylylene containing a substituted chlorineatom, and can be used to create a moisture barrier on the surface of amedical device. Parylene C can be coated by delivering it in a vacuumenvironment at low pressure as a gaseous polymerizable monomer. Themonomer condenses and polymerizes on substrates at room temperature,forming a matrix on the surface of the medical device. The coatingthickness is controlled by pressure, temperature, and the amount ofmonomer used, in order to provide an inert, non-reactive barrier. Inaddition, supports such as those formed of pyrolytic carbon andsilylated surfaces of glass, ceramic, or metal are suitable for surfacemodification.

Such materials can be used to fabricate a number of devices capable ofbeing provided, either before, during and/or after their fabrication,with a polymeric coating according to the present invention. Suchdevices are typically adapted to be used on either a permanent ortransitory basis, and either within or upon the body. Such devices canbe entirely coated with the present reagent, or have particular portionsor components thus coated.

Medical devices, including those adapted for use within or upon thebody, include either those permanently implanted in the body forlong-term use or used temporarily in the body are one general class ofsuitable devices, and include but are not limited to the following.

Long-term devices including grafts, stents, stent/graft combinations,valves, heart assist devices, shunts, and anastomoses devices; catheterssuch as central venous access catheters; orthopedic devices-such asjoint implants, fracture repair devices, and artificial tendons, dentalimplants and dental fracture repair devices; intraocular lenses;surgical devices such as sutures and patches; synthetic prosthesis; andartificial organs such as artificial lung, kidney, and heart devices.

Short-term devices including vascular devices such as distal protectiondevices; catheters such as acute and chronic hemodialysis catheters,cooling/heating catheters, and percutaneous transluminal coronaryangioplasty (PTCA) catheters; ophthalmic devices such as contact lensesand glaucoma drain shunts.

Similarly, non-implanted biomedical devices can be coated, in whole orin part, using a reagent of the present invention, including but notlimited to the following. Diagnostic slides such as gene chips, DNA chiparrays, microarrays, protein chips, and fluorescence in situhybridization (FISH) slides; arrays, including cDNA arrays andoligonucleotide arrays; blood sampling and testing components;functionalized microspheres; tubing and membranes, e.g., for use indialysis or blood oxygenator equipment; and blood bags, membranes, cellculture devices, chromatographic support materials, biosensors, and thelike.

The method and reagent of this invention are particularly well suitedfor coating devices such as distal protection devices (also known asemboli catching devices), e.g., of the type described in U.S. Pat. No.6,245,089, the disclosure of which is incorporated herein by reference

The present invention provides improved control over the in situpolymerization process, by the use of latent reactive (e.g.,photoreactive) species that are capable of serving as both latentreactive (e.g., photoreactive) groups (sufficient to covalently attachthe reagent to a surface) and as photoinitiators (e.g., photoinitiatinggroups to initiate polymerization). As described herein, photoinitiatinggroups can be provided by the grafting reagent itself, instead of (oroptionally, in addition to) being separately provided in solution or bya preformed polymer to be attached to the support surface. Thephotoinitiating groups of the present invention are adapted toregeneratively participate in the polymerization process.

In a particularly preferred embodiment, the latent reactive (e.g.,photoreactive) species are adapted to undergo reversible photolyticactivation, thereby permitting latent reactive (e.g., photoreactive)species that are not consumed in attachment to the support surface torevert to an inactive, or “latent” state. These latent reactive (e.g.,photoreactive) species can be subsequently activated, in order to serveas photoinitiator groups for initiating free radical polymerization.Thus, excitation of the photoinitiator is reversible and the group canreturn to a ground state energy level upon removal of the energy source.Particularly preferred photoinitiators are those groups that are subjectto multiple activation in suitable (typically aqueous) systems and henceprovide increased coating efficiency.

In another preferred embodiment, the photoinitiating species are adaptedto undergo a homolytic alpha cleavage reaction between a carbonyl groupand an adjacent carbon atom. This type of reaction is generally referredto as a Norrish type I reaction.

In another embodiment, the photoinitiating species is a photosensitizer.Photosensitizers are generally photoreducible or photo-oxidizable dyes.In most instances, photoreducible dyes are used in conjunction with areductant, typically a tertiary amine. The reductant intercepts theinduced triplet, producing the radical anion of the dye and the radicalcation of the reductant.

A typical free radical polymerization comprises four steps: initiation,propagation, termination, and chain transfer. In initiation, a freeradical derived from an initiator adds to a monomer molecule to form anactive center. Other initiating reactions include addition to the headof the molecule or hydrogen abstraction, and the reaction mechanismdepends upon the structures of the radical and monomer. The propagationor growth reaction consists of the rapid addition of monomer moleculesto the radical species. The most common mechanism of propagation occursin head-to-tail fashion. However, propagation may also occur inhead-to-head, tail-to-head, and tail-to-tail modes. In termination, thepolymer chain stops growing by the destruction of propagating radicals.Normally, in the absence of species that destroy radicals, chaintermination occurs by bimolecular interaction of radicals (e.g., radicalcombinations or disproportionation).

In a preferred embodiment, the grafting reagent comprises a restrained,multifunctional grafting reagent, the preparation of which is describedin Applicant's U.S. Pat. No. 5,414,075, the entire disclosure of whichis incorporated herein by reference. Such a reagent can be used toinitially derivatize the support surface, prior to contacting thesurface with polymerizable monomer.

A grafting reagent of this preferred type comprises a chemicalnonpolymeric core molecule having attached to it one or more firstlatent reactive groups and one or more second latent reactive groups,each of the first and second latent reactive groups being attached tothe backbone in such a manner that, upon activation of the latentreactive groups in the presence of a support surface,

a) the first latent reactive groups are capable of covalently bonding tothe support surface, and

b) upon bonding of the first latent reactive groups to the surface, thesecond latent reactive groups are;

i) restricted from reacting with either a spacer or the support surface,

ii) capable of reverting to their inactive state, and

iii) upon reverting to their inactive state, are thereafter capable ofbeing reactivated in order to later initiate polymerization of monomers,thereby forming a polymer on the surface.

The first and second latent reactive groups can be of the same ordifferent types, and as previously, the distinction between the two canbe determined under the conditions, and at the time of use. Generally,the first latent reactive groups are defined (from amongst thoseoriginally present) as those that become attached to the surface itself,which in turn, serves to define the second latent reactive groups asthose that remain unattached, and hence revert to activatable form. Inthe present invention, Applicants have found that those second latentreactive groups are particularly well suited to serve as photoinitiatorsfor a polymerization reaction. Without intending to be bound by theory,it appears that the utility of such reagents for use in grafting isimproved also by the reagent's lack of solubility in polar solvent. In aparticularly preferred embodiment, the grafting reagent of the inventionis selected from the group consisting of tetrakis(4-benzoylbenzylether), the tetrakis(4-benzoylbenzoate ester) of pentaerythritol, and anacylated derivative of tetraphenylmethane.

In an alternative embodiment, the present invention provides a coatingagent comprising a nonpolymeric core molecule having attached thereto,either directly or indirectly, one or more substituents comprisingnegatively charged groups, and two or more latent reactive species,wherein the latent reactive species are provided as discrete latentreactive groups. In such an embodiment, the latent reactive speciescomprise one or more first latent reactive species adapted to attach thecoating agent to a surface, and one or more second latent reactive(e.g., photoreactive) species adapted to initiate photopolymerization.Suitable reagents of this type are described, for instance, inApplicant's International Patent Application No. US 99/21247, thedisclosure of which is incorporated herein by reference.

In one such embodiment, the coating agent comprises a conjugated cyclicdiketone having attached thereto, either directly or indirectly, one ormore substituents comprising negatively charged groups, and wherein eachketone group of the diketone is adapted to serve as a photoreactivemoiety capable of being activated in order to provide a free radical.Preferably, the conjugated cyclic diketone is a quinone selected fromsubstituted and unsubstituted benzoquinone, camphorquinone,naphthoquinone, and anthraquinone.

Such reagents typically comprise a nonpolymeric core molecule havingattached thereto, either directly or indirectly, one or moresubstituents comprising negatively charged groups, and two or morelatent reactive species, wherein the latent reactive species areprovided as discrete photoreactive groups. In a preferred embodiment,such coating agents are selected from the group4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic aciddipotassium salt (DBDS),2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic aciddipotassium salt (DBHQ), a hydroquinone monosulfonic acid derivative, ananthraquinone sulfonic acid salt, and a camphorquinone derivative.Optimally, the coating agent is selected from DBDS, DBHQ, and2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-sulfonic acid mono (ordi-) sodium salt.

Particularly preferred grafting reagents of this type are selected fromthe group 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonicacid dipotassium salt (DBDS), and2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic aciddipotassium salt (DBHQ).

In another alternative embodiment, a grafting reagent of the presentinvention can be provided in the form of a reagent of the generalformula:X—Y—Xwherein each X is independently a radical containing a latent reactive(e.g., photoreactive) group and Y is a radical containing one or morecharged groups. Such reagents are described, for instance, inApplicant's U.S. Pat. No. 5,714,360, the disclosure of which isincorporated herein by reference.

A reagent of this type includes one or more charged groups, andoptionally one or more additional latent reactive (e.g., photoreactive)groups, included in the radical identified in the empirical formula as“Y.” A “charged” group, when used in this sense, refers to groups thatare present in ionic form, i.e., carry an electrical charge under theconditions (e.g., pH) of use. The charged groups are present, in part,to provide the compound with the desired water solubility.

Preferred Y groups are nonpolymeric, that is, they are not formed bypolymerization of any combination of monomers. Nonpolymeric agents arepreferred since they will tend to have lower molecular mass, which inturn means that they can generally be prepared to have a higherconcentration of latent reactive groups per unit mass. In turn, they cangenerally provide a higher coating density of latent reactive groupsthan comparable latent reactive polymeric agents.

The type and number of charged groups in a preferred agent aresufficient to provide the agent with a water solubility (at roomtemperature and optimal pH) of at least about 0.1 mg/ml, and preferablyat least about 0.5 mg/ml, and more preferably at least about 1 mg/ml.Given the nature of the surface coating process, linking agentsolubility levels of at least about 0.1 mg/ml are generally adequate forproviding useful coatings of target molecules on surfaces.

Examples of suitable charged groups include, but are not limited to,salts of organic acids (such as sulfonate, phosphonate, and carboxylategroups), onium compounds (such as quaternary ammonium, sulfonium, andphosphonium groups), and protonated amines, as well as combinationsthereof. An example of an agent employing charged groups other thanquaternary ammonium compounds is provided in Formula X of Table I in the'360 patent, the disclosure of which is incorporated herein byreference. By reference to the empirical formula provided above, it canbe seen that R³ in Formula X would be a lone pair of electrons, in orderto provide a tertiary amine group, and R² would contain a chargedsulfonate group in a radical of the formula —CH₂—CH₂—SO₃Na. Sufficientoverall charge to render the compound water soluble is provided by thenegative charge of the remote sulfonate group.

A preferred charged group for use in preparing compounds of the presentinvention is a quaternary ammonium group. The term “quaternaryammonium,” as used herein, refers to organic derivatives of NH₄ ⁺ inwhich the hydrogen atoms are each replaced by radicals, therebyimparting a net positive charge on the radical. The remainingcounter-ion can be provided by any suitable anionic species, such as achloride, bromide, iodide, or sulfate ion.

In a preferred embodiment two or more photoreactive groups are providedby the X groups attached to the central Y radical. Upon exposure to asuitable light source, each of the photoreactive groups are subject toactivation. The term “photoreactive group,” as used herein, refers to achemical group that responds to an applied external ultraviolet orvisible light source in order to undergo active specie generation,resulting in covalent bonding to an adjacent chemical structure (via anabstractable hydrogen).

Preferred reagents of this type are selected from the groupethylenebis(4-benzoylbenzyldimethylammonium)dibromide (Diphoto-Diquat);hexamethylenebis(4-benzoylbenzyldimethylammonium)dibromide(Diphoto-Diquat); 1,4-bis(4-benzoylbenzyl)-1,4-dimethylpiperazinediiumdibromide (Diphoto-Diquat);bis(4-benzoylbenzyl)hexamethylenetetraminediium dibromide(Diphoto-Diquat);bis[2-(4-benzoylbenzyldimethylammonio)ethyl]-4-benzoylbenzylmethylammoniumtribromide (Triphoto-Triquat); 4,4-bis(4-benzoylbenzyl)morpholiniumbromide (Diphoto-Monoquat);ethylenebis[(2-(4-benzoylbenzyldimethylammonio)ethyl)-4-benzoylbenzylmethylammonium]tetrabromide(Tetraphoto-Tetraquat); 1,1,4,4-tetrakis(4-benzoylbenzyl)piperazinediiumDibromide (Tetraphoto-Diquat); andN,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid, sodiumsalt (Diphoto-Monosulfonate), and analogues (including those havingalternative counter ions) thereof, corresponding to Compounds II throughX, respectively, of the above-captioned '360 patent. Terms such as“Diphoto-Diquat” are used herein to summarize the number of respectivegroups (e.g., photo groups, quaternary ammonium groups, etc.) perreagent molecule.

A “latent reactive group,” as used herein, refers to a chemical groupthat responds to an applied external energy source in order to undergoactive specie generation, resulting in covalent bonding to an adjacentchemical structure (via an abstractable hydrogen). Preferred groups aresufficiently stable to be stored under conditions in which they retainsuch properties. See, e.g., U.S. Pat. No. 5,002,582, the disclosure ofwhich is incorporated herein by reference. Latent reactive groups can bechosen that are responsive to various portions of the electromagneticspectrum, with those responsive to ultraviolet and visible portions ofthe spectrum (referred to herein as “photoreactive”) being particularlypreferred.

Photoreactive species respond to a specific applied external ultravioletor visible light source to undergo active specie generation withresultant covalent bonding to an adjacent chemical structure, e.g., asprovided by the same or a different molecule. Photoreactive species arethose groups of atoms in a molecule that retain their covalent bondsunchanged under conditions of storage but that, upon activation by aspecific applied external ultraviolet or visible light source, formcovalent bonds with other molecules.

Latent reactive (e.g., photoreactive) species generate active speciessuch as free radicals and particularly nitrenes, carbenes, and excitedstates of ketones upon absorption of electromagnetic energy. Latentreactive (e.g., photoreactive) species can be chosen to be responsive tovarious portions of the electromagnetic spectrum, and photoreactivespecies that are responsive to the ultraviolet and visible portions ofthe spectrum are preferred and can be referred to herein occasionally as“photochemical group” or “photogroup.”

The latent reactive (e.g., photoreactive) species in latent reactive(e.g., photoreactive) aryl ketones are preferred, such as acetophenone,benzophenone, anthraquinone, anthrone, and anthrone-like heterocycles(i.e., heterocyclic analogs of anthrone such as those having N, O, or Sin the 10-position), or their substituted (e.g., ring substituted)derivatives. Examples of preferred aryl ketones include heterocyclicderivatives of anthrone, including acridone, xanthone, and thioxanthone,and their ring substituted derivatives. Particularly preferred arethioxanthone, and its derivatives, having excitation energies greaterthan about 360 nm.

The functional groups of such ketones are preferred since they arereadily capable of undergoing the activation/inactivation/reactivationcycle described herein. Benzophenone is a particularly preferred latentreactive (e.g., photoreactive) moiety, since it is capable ofphotochemical excitation with the initial formation of an excitedsinglet state that undergoes intersystem crossing to the triplet state.The excited triplet state can insert into carbon-hydrogen bonds byabstraction of a hydrogen atom (from a support surface, for example),thus creating a radical pair. Subsequent collapse of the radical pairleads to formation of a new carbon-carbon bond. If a reactive bond(e.g., carbon-hydrogen) is not available for bonding, the ultravioletlight-induced excitation of the benzophenone group is reversible and themolecule returns to ground state energy level upon removal of the energysource. Photoactivatible aryl ketones such as benzophenone andacetophenone are of particular importance inasmuch as these groups aresubject to multiple reactivation in water and hence provide increasedcoating efficiency.

The method of the present invention involves the attachment of apolymerizable compound to a support surface by use of theabove-described grafting reagent. As will be discussed more fully below,the grafting reagent can be used in a number of different ways toachieve the desired result.

In one embodiment, the present invention provides a system comprising agrafting reagent as described herein, and a plurality of molecules, eachbearing one or more polymerizable groups. In accordance with thisembodiment, the photoinitiator group serves to initiate polymerizationof the polymerizable groups, thereby forming a polymeric coating, e.g.,in the form of a layer covalently bound to the support surface of adesired article via the grafting reagent. As used herein, “polymerizablegroup” shall generally refer to a group that is adapted to bepolymerized by initiation via free radical generation, and morepreferably by photoinitiators activated by visible or long wavelengthultraviolet radiation.

Suitable polymerizable compounds can be used to provide polymerizationproducts (e.g., a polymeric coating resulting from free radicalpolymerization) that are either inherently hydrophilic or are capable ofbeing readily modified to provide hydrophilic characteristics atappropriate reaction conditions (e.g., pH). Moreover, the polymerizablegroups of such compounds can include those adapted to participate infree-radical polymerization. Preferred compounds include at least onefree-radical polymerizable component (e.g., a vinyl group), and at leastone functional group with a high affinity for water. As contemplated bythe present invention, such functional groups with a high affinity forwater can be negatively charged, positively charged, or electricallyneutral.

Suitable polymerizable compounds are selected from monomericpolymerizable molecules (e.g., organic monomers), and macromericpolymerizable molecules (e.g., organic macromers). As used herein,“macromer” shall refer to a macromolecular monomer having a molecularweight of about 250 to about 25,000, and preferably from about 1,000 toabout 5,000. For purposes of the present invention, and unless specifiedotherwise, the term “monomer” when used in this respect shall generallyrefer to monomeric and/or macromolecular polymerizable molecules.

Suitable polymerizable compounds can contain neutral hydrophilicfunctional units, for example, acrylamide and methacrylamidederivatives. Examples of suitable monomers containing electricallyneutral hydrophilic structural units include acrylamide, methacrylamide,N-alkylacrylamides (e.g., N,N-dimethylacrylamide or methacrylamide),N-vinylpyrrolidinone, N-vinylacetamide, N-vinyl formamide,hydroxyethylacrylate, hydroxyethylmethacrylate, hydroxypropyl acrylateor methacrylate, glycerolmonomethacrylate, and glycerolmonoacrylate.

Alternatively, suitable polymerizable compounds containing electricallycharged hydrophilic functional units include molecules whose polymers,once formed, can be readily modified (e.g., by hydrolysis) to provideproducts with enhanced affinity for water. Examples of suitable monomersof this type include glycidyl acrylate or methacrylate, whose polymersbear epoxy groups that can be readily hydrolyzed to provide glycolstructures having a high affinity for water. Examples of suitablemonomeric polymerizable molecules that are negatively charged atappropriate pH levels include acrylic acid, methacrylic acid, maleicacid, fumaric acid, itaconic acid, AMPS (acrylamidomethylpropanesulfonic acid), vinyl phosphoric acid, vinylbenzoic acid, and the like.

Alternatively, suitable monomeric polymerizable molecules that arepositively charged at appropriate pH levels include molecules whosepolymers, once formed, can be readily modified to provide products withenhanced affinity for water. Examples of suitable monomeric moleculesthat are positively charged at appropriate pH levels include3-aminopropylmethacrylamide (APMA),methacrylamidopropyltrimethylammonium chloride (MAPTAC),N,N-dimethylaminoethylmethacrylate, N,N-diethylaminoethylacrylate, andthe like.

Alternatively, suitable positively charged monomeric polymerizablemolecules include those molecules that can be readily modified toprovide products with enhanced affinity for water as well as a positivecharge, e.g., glycidyl methacrylate whose polymeric products can bereacted with amines (e.g., ethylamine), to provide hydroxyaminocompounds. In some cases, these materials will contain a structural unitwith an inherent positive charge, as for example with fully quaternizedammonium structures. In other cases, the positively charged structuralunit will exist at certain pH values, particularly at acidic pH values.

In yet another embodiment, the polymerizable monomer compounds of thepresent invention comprise macromeric polymerizable molecules. Suitablemacromers can be synthesized from monomers such as those illustratedabove. According to the present invention, polymerizable functionalcomponents (e.g., vinyl groups) of the macromer can be located at eitherterminus of the polymer chain, or at one or more points along thepolymer chain, in a random or nonrandom structural manner.

The number of free-radical polymerizable groups per molecule can bevaried according to the application. For example, it can be preferableto employ a macromer with just one free-radical polymerizable unit. Inother instances, however, it can be preferable to employ a macromer withmore than one, e.g., two or more polymerizable units per macromer.Additionally, the macromer of the present invention can containstructural features to provide improved affinity for water in a mannertypically unavailable in small molecule structures (e.g., hydrophilicpoly(ethylene glycol) materials). Examples of suitable macromericpolymerizable compounds include methacrylate derivatives, monoacrylatederivatives, and acrylamide derivatives. Particularly preferredmacromeric polymerizable compounds include poly(ethyleneglycol)monomethyacrylate, methoxypoly(ethylene glycol)monomethacrylate,poly(ethylene glycol)monoacrylate, methyacrylamidopoly(acrylamide),poly(acrylamide-co-3-methacrylamidopropylacrylamide),poly(vinylalcohol)methacrylate, poly(vinylalcohol)acrylate,poly(vinylalcohol)dimethacrylate, and the like.

Such macromers can be prepared, for instance, by first synthesizing ahydrophilic polymer of the desired molecular weight, followed by apolymer modification step to introduce the desired level ofpolymerizable (e.g., vinyl) functional units. For example, acrylamidecan be copolymerized with specific amounts of3-aminopropylmethacrylamide comonomer, and the resulting copolymer canthen be modified by reaction with methacrylic anhydride to introduce themethacrylamide functional units, thereby producing a useful macromer forpurposes of this invention.

Poly(ethylene glycol) of a desired molecular weight can be synthesizedor purchased from a commercial source, and modified (e.g., by reactionwith methacrylyl chloride or methacrylic anhydride) to introduce theterminal methacrylate ester units to produce a macromer useful in theprocess of this invention. Some applications can benefit by use ofmacromers with the polymerizable units located at or near the terminusof the polymer chains, whereas other uses can benefit by having thepolymerizable unit(s) located along the hydrophilic polymer chainbackbone.

Such monomeric and macromeric polymerizable molecules can be used aloneor in combination with each other, including for instance, combinationsof macromers with other macromers, monomers with other monomers, ormacromers combined with one or more small molecule monomers capable ofproviding polymeric products with the desired affinity for water.Moreover, the above polymerizable compounds can be provided in the formof amphoteric compounds (e.g., zwitterions), thereby providing bothpositive and negative charges.

A preferred method of this invention includes the step of applying thegrafting reagent and monomer solution to the surface in a manner, andunder conditions, suitable to coat the surface, which preferablyincludes pores. The method also includes the step of contacting thesurface with polymerizable monomers, typically in solvent or othersolution form, and illuminating the surface in order to cause thepolymerization of monomers to the surface upon activation of thegrafting reagent.

Grafting reagents of the present invention can be used in any suitablemanner, e.g., by simultaneous or sequential attachment of the graftingreagent and polymerizable monomers to a support surface. In a preferredembodiment, the method of this invention involves a two-step process,involving sequential steps in which grafting reagent is first attachedto the surface, after which compounds are polymerized thereon using thephotoinitator of the attached agent. One advantage of a sequentialapproach is that photopolymerization of this sort allows the generationof thin polymeric coatings on the support surface. The resultantpolymeric coating is typically highly adherent, uniform in thickness,and is highly durable. Moreover, solutions used to form the polymericcoating can be applied (e.g., via in solution application, dipping,spray coating, knife coating, and roller coating) to any suitablesupport surface of any surface morphology. The resultant polymericcoating, in turn, can be adapted to cover irregular surfaces as well assmooth, relatively uniform surfaces.

Grafting reagents as described herein can be used to modify any suitablesurface. Where the latent reactive group of the agent is a latentreactive (e.g., photoreactive) group of the preferred type, the supportsurface to be coated preferably provides abstractable hydrogen atomssuitable to enable covalent bonding with the activated group. In anotherembodiment, the surface can be modified (e.g., by pretreatment with asuitable reagent) to provide abstractable hydrogen atoms on the surface.

The steps of the method can be performed in any suitable order. Forexample, a multifunctional grafting reagent as described above canphysically adhere itself to a suitable support surface by hydrophobicinteractions. Upon illumination, the photoreactive groups (e.g.,benzophenone groups) undergo covalent bond formation at the supportsurface by the aforementioned mechanism. With the absence ofabstractable hydrogens in proximity to the remaining unbondedphotoreactive group(s), and removal of the illumination source, theexcited state benzophenone returns to ground state energy. Theseremaining groups are then capable of being reactivated when thepolymerizable compound intended for immobilization is present and whenthe treated surface is exposed to another round of illumination. Thismethod can be described as a “two-step” approach, where thephotoreactive grafting reagent is applied in the first step to createthe latent reactive surface, and in the second step, the polymerizablecompound is added for attachment to the activated surface.

The invention will be further described with reference to the followingnon-limiting Examples. It will be apparent to those skilled in the artthat many changes can be made in the embodiments described withoutdeparting from the scope of the present invention. Thus the scope of thepresent invention should not be limited to the embodiments described inthis application, but only by embodiments described by the language ofthe claims and the equivalents of those embodiments. Unless otherwiseindicated, all percentages are by weight.

EXAMPLE 1 Surface Modification of Polyurethane (PU) by Application ofAcrylamide/Acrylamidomethylpropane Sulfonic Acid (AMPS) with Compound I

Compound I was prepared according to the method described in Example 1of U.S. Pat. No. 5,414,075. A coating solution was prepared bydissolving an amount of Compound I at 1 g/l in 100% isopropyl alcohol(IPA). Polyurethane rods (5 cm (2 in.) long, Thermedics) were wiped withan IPA (99% purity) soaked lint-free cloth and allowed to dry. The cleanPU rods were then dipped into the Compound I solution, previouslyprepared as described above, removed from the solution at a steady rate(approximately 2 cm/sec), and allowed to dry for at least 5 minutes.

After applying Compound I to the rods, the rods were placed in asolution containing a mixture of monomers (acrylamide 3% or 7% and AMPS7% or 3% respectively, weight to volume) in deionized (DI) water.Approximately 8 ml of the monomer mixture was placed in a glass syringe(10 ml, Micro-mate™ interchangeable hypodermic syringe with lever lock,Popper and Sons, Inc.) containing a stopcock in the bottom to preventthe solution from draining out. The PU rods were placed in the syringecontaining the monomer solution and nitrogen gas was allowed to bubbleup into the solution for at least 10 minutes to remove oxygen in thesolution. After deoxygenating, the solution containing the PU rods wasexposed to UV light (EFOS light—Ultracure 100 SS Plus systems with lightguide, EFOS USA Inc. in the 320-500 nm wavelength range for 150seconds). The intensity of the light, as measured with a radiometer(International Light, IL1400A with SEL005/NS335/W), was approximately 20mw/cm² in the 330-340 nm wavelength measured at a distance of 2.5-3.0 cmfrom the end of the light source. After exposure to the UV light, thesamples were removed from the monomer solution and washed thoroughly toremove any unbound residual monomer.

Lubricity and Durability

After coating, the PU rods were evaluated for lubricity/durability byfriction measurements using a Vertical Pinch Method (FIG. 1) describedas follows: The coated PU rods were inserted into the end of a rodholder which was placed between the two jaws of a pinch tester which wasimmersed in a cylinder of water or saline. The jaws of the pinch testerwere closed as the sample was pulled in a vertical direction and openedwhen the coated sample was returned to the original position. A 300 gforce (load) was applied as the sample rod was pulled up through thepinched jaws. The average frictional force was determined for 15 cycleswhile the coated rod traveled 3 cm at a travel rate of 0.5 mm/sec. Theresults shown in Table 1 indicate that the applied coating improved thelubricity of the rods as compared to uncoated controls. The results alsoshow that the coating remained lubricious over the 15 cycles indicatingthat the coating was also durable.

TABLE 1 Lubricity/Durability Testing Cycle 1 Cycle 15 % Force FrictionFriction % Increase Average of Reduction Force Force (Cycle 1 15 Cycles(compared to Substrate (grams) (grams) to 15) (grams) uncoated)Polyurethane - — — — 190.6 uncoated n = 1 Polyurethane - graft 6.7 6.5−2.7 6.5 96.6 coating (7% AMPS 3% Acrylamide) n = 3 PEBAX - uncoated — —— 190.3 n = 2 PEBAX - graft 9.1 10.2 12.2 9.5 95.0 coating (7% AMPS 3%Acrylamide) n = 3 Silicone - uncoated — — — 157.6 — n = 3 Silicone -graft 21.5 19.4 −9.8 19.1 87.9 coating (3% AMPS 7% Acrylamide) N = 8

TABLE 2 Bacterial Adherence Assay % Reduction compared to P value(one-tailed, Substrate Organism uncoated (n = 6) alpha = 0.05)Polyurethane S. epidermidis 97.9 0.0034 Polyurethane C. albicans 99.10.0392 Polyurethane P. mirabilis 99.6 0.0063 PEBAX S. epidermidis 96.70.1104 PEBAX C. albicans 96.0 0.0167 PEBAX P. mirabilis 99.6 0.1112Silicone S. epidermidis 82.8 0.0408

Bacterial Adherence Assays

Bacterial adherence assays of the resulting coated PU rods wereperformed in the following manner. Three strains of bacteria,Pseudomonas mirabilis (ATCC 35506), Staphylococcus epidermidis (ATCCRP62A), and Candida albicans (ATCC 64550) were examined with the coatedrods. Samples were individually placed into snap-cap tubes whereuponthree milliliters of 1×10⁷ CFU/ml prepared suspension of each bacteriawas added. Tubes were placed in a rack onto an orbital shaker set at 150rpm for two hours. Samples were then removed from the tubes and placedinto 50 ml screw cap centrifuge tubes in like groups with 40 ml ofphosphate buffered saline (PBS, pH 6.8) at room temperature. Caps werescrewed on and samples were placed on an orbital shaker at 200 rpm fortwo minutes. The PBS was decontaminated and this step was repeated threemore times. After completion of the wash step, the samples were placedon 100% IPA treated Kimwipes® and dried in a laminar flow hood onKimwipes® before being imbedded into molten (55° C.) Tryptic Soy Agarwith 0.001% TTC (2,3,5-triphenyltetrazolium chloride, Difco). Thesolidified agar plates were placed in a 37° C. incubator overnight andthe colonies were counted the following day. Each sample was sectionedinto 8 pie pieces by hand, drawing lines on the petri dish directlyabove the samples. With the use of a stereoscope and a hand tallycounter, each section was counted for colony forming units and thepercent reduction as compared to uncoated sample was determined. Asindicated in Table 2, the coated rods were significantly less adherentto the three organisms tested as compared to uncoated surfaces.

EXAMPLE 2 Surface Modification of Polyether Block Amide (PEBAX) byApplication of Acrylamide/AMPS with Compound I

A coating solution was prepared by dissolving Compound I as described inExample 1. PEBAX rods (5 cm O.D. 118, Light Blue, 20% Barium Sulfate,Medical Profiles Inc.) were coated as described in Example 1 except therods were allowed to soak for approximately 30 minutes in Compound Icoating solution. The results for lubricity/durability and bacterialadherence are shown on Table 1 and Table 2, respectively. The resultsshown in Table 1 indicate that the applied coating improved thelubricity of the rods as compared to uncoated controls. The results ofTable 2 indicated that the control rods were not adherent to the threeorganisms tested, as compared to uncoated rods.

EXAMPLE 3 Surface Modification of Silicone Rubber (SR) by Application ofAcrylamide/AMPS with Compound I

A coating solution containing Compound I was prepared as described inExample 1. SR rods (5 cm, SSF-19ETD-750, Specialty Silicone Fabricators)were coated by the same procedure as in Example 1 with the followingexceptions. The SR rods to be coated were sonicated in an IPA solutionfor at least 10 minutes. After sonication, the rods were allowed to dryfor 2 to 3 hours. The rods were also cleaned with an EPA-soakedlint-free cloth prior to coating with Compound I coating solution. TheSR rods were allowed to soak for approximately 30 minutes in theCompound I coating solution. The experimental results for bothlubricity/durability and bacterial adherence properties are shown inTable 1 and Table 2, respectively. The results shown in Table 1 andTable 2 indicate that the coated rods were more lubricious andsignificantly less adherent to the three organisms as compared withuncoated controls.

EXAMPLE 4 Surface Modification and Analysis of Low Density Polyethylene(LDPE) by Application of Acrylamide/AMPS with Compound I

Low density polyethylene (LDPE) was precoated with a solution containingCompound I. The polyethylene substrate was obtained as flat sheets(0.3/mm thick), and used as ½ inch diameter disks. The coating solutionof Compound I was prepared and coated on the LDPE surface as describedin Example 1. After precoating, the LDPE disks were coated withacrylamide/AMPS as previously described (Example 1), after which thecoated LDPE pieces were stained in 0.1% Toluidine Blue (Sigma, PN:T3260)for approximately 60 seconds. Visual examination revealed that thecoated LDPE material was evenly stained blue, indicating an even anduniform coating. The coated samples were then tested forhemocompatibility using the protocols described below.

Platelet Attachment and Activation from Platelet Rich Plasma

Various samples of the surface-modified materials described above wereincubated with platelet rich plasma (PRP), observed with fluorescentmicroscopy, and imaged with a digital camera to determine the influenceof surface chemistry on platelet activation and attachment. Blood wascollected fresh from human volunteers into tubes (Vacutainer bloodcollection tubes, Baxter, product #369705) containing 3.8% (v/v) sodiumcitrate solution using 9:1 ratio of blood to anticoagulant. The bloodwas centrifuged at 1200 rpm for 15 minutes to separate PRP from blood.The PRP was collected and kept (less than 1 hour) at room temperatureuntil used.

The test samples (1.5 cm×1.5 cm) were placed in a 12-well plate, 1sample per well. The PRP solution was added to the samples (150 μl)until the entire surface of each sample was covered, and the sampleswere then incubated one hour at room temperature with no agitation.After incubation, the PRP was removed carefully by aspiration and 3 mlof Tyrode's buffer (138 mM NaCl, 2.9 mM KCl, 12 mM sodium bicarbonate,1% (w/v) glucose, pH 7.4) was gently added to each well. The plates wereagitated slightly on an orbital shaker for 15 minutes; the solution waschanged and the wash repeated. The wash solution was aspirated and 2 mlof 3.7% (v/v) formaldehyde in phosphate buffered saline (PBS) (2 mMKH₂PO₄, 8 mM K₂HPO₄, 150 mM NaCl, pH 7.4) were added to each well. Theplates were incubated for 20 minutes with slight agitation on an orbitalshaker at room temperature.

The formaldehyde solution was aspirated off and the samples were rinsedonce in deionized water. The cell membranes of the platelets werepermeabilized by adding 1 ml of a solution of 1% (v/v) Triton-X 100(t-octylphenoxypolyethoxyethanol, Sigma 9002-93-1) in PBS and incubatedfor 15 minutes on an orbital shaker at room temperature. The Triton-X100 solution was aspirated off of the samples and the samples wererinsed three times with 3 ml PBS each. Phalloidin-Texas Red stock(Molecular Probes, T-7471) was diluted 1:80 in PBS and 400 μl was addedto each sample. The plate was incubated in the dark for 20 minutes withslight agitation on an orbital shaker at room temperature. Samples wererinsed 3 times with 3 ml PBS each and once with deionized water. Sampleswere kept in deionized water until they were viewed with a fluorescencemicroscope. Images were taken of different areas of the sample with adigital camera at a magnification of 500× to give a representative viewof each sample. Percent platelet coverage was measured by analyzingimages using Image-Pro Plus software (Media Cybernetics). See Table 3.

TABLE 3 Platelet Attachment % Reduction % Platelet Standard (compared toSample Coverage (n = 3) Deviation uncoated) Uncoated exp 1 62.3 3.1 —Compound I, 7/3 2 0 97 Acrylamide/AMPS - exp 1 Uncoated exp 2 54 10.4 —Compound I, 7/3 0.4 0.5 99 Acrylamide/AMPS - exp 2

Fibrinogen Adsorption out of Platelet Poor Plasma (PPP)

Fibrinogen adsorption was quantified using an ELISA technique. First,fibrinogen was adsorbed to samples (uncoated and surface-modified) outof human plasma. Second, the adsorbed fibrinogen was then challengedwith a polyclonal anti-human-fibrinogen-HRP (horseradish peroxidase)conjugate. The antibody conjugate generated color upon the addition ofchromogenic substrate. Absorbances were then measured using aspectrophotometer. The amount of color generation was proportional tothe amount of fibrinogen adsorbed.

Samples were placed in 12×75 mm glass test tubes (3 samples/test tube).One milliliter of human platelet poor plasma (George King Bio-Medical,pooled normal plasma) was added to each test tube. Samples wereincubated for 2 hours with agitation on an orbital shaker at roomtemperature. The plasma was aspirated off of the samples and the sampleswere washed 2 times with TNT wash solution (50 mM Tris, 150 mM NaCl,0.05%. (v/v) Tween 20, pH 7.5). One milliliter of polyclonalanti-human-fibrinogen-HRP (BioDesign, product # K90056P) was added toeach test tube at a dilution of 1:10,000 in Tris-saline (TN) bufferedsolution (50 mM Tris, 150 mM NaCl, 0.05% (v/v)). Samples were incubatedfor 30 minutes with agitation on an orbital shaker at room temperature.The antibody solution was aspirated off and the samples were washedthree times with TNT wash solution.

Samples were then transferred to clean 12×75 mm glass test tubes (1sample/test tube) and 1 ml of tetramethylbenzidine (TMB) substratesolution and hydrogen peroxide were added to each test tube. The sampleswere incubated for 15 minutes with agitation on an orbital shaker atroom temperature. The supernatant was then transferred to a 96-wellmicrotiter plate and the absorbances at 650 mm were read on aspectrophotometer (Molecular Devices, Thermomax microplate reader) witha negative control solution containing chromogen but no conjugate usedas the blank. The absorbances are directly proportional to the surfaceconcentration of HRP and, therefore, also proportional to the surfaceconcentration of fibrinogen bound to the surface of the materials. Theresults are shown in Table 4.

TABLE 4 Fibrinogen binding Mean ± SD (Absorbance % Reduction (comparedSample at 650 nm) n = 3 to uncoated) Uncoated 0.294 ± 0.024 — CompoundI, 7/3 0.113 ± 0.019 61 Acrylamide/AMPS

Factor XIIa Generation—A Measure of Contact Activation

The uncoated and surface-modified low-density polyethylene (LDPE)samples were assayed for Factor XIIa (activated Factor XII) generation,a measure of contact activation of the intrinsic coagulation cascade.Human plasma was incubated on samples for 1 hour. Samples of the plasmawere removed and transferred to a 96-well plate. A chromogenic substratethat is specific for factor XIIa was added to the wells. Absorbanceswere measured using a spectrophotometer and factor XIIa generation wasproportional to the amount of color generated.

Human platelet-poor plasma (George King Bio-Medical Inc., pooled normalplasma) was diluted 4 times in Tris-buffered saline (TBS), 50 mM Tris,150 mM NaCl, pH 7.5, to obtain 25% plasma. Samples (25 mm diameteruncoated LDPE, surface-modified LDPE, and glass disks) were placed in a6-well plate (1 disk/well). Glass disks served as a positive controlbecause factor XII is greatly activated by negatively charged surfaces.500 μl aliquots of 25% plasma were carefully placed on the disks toensure the plasma only contacted the disks and not the 6-well plate. Thesamples were incubated for 2 hours at room temperature with noagitation. The incubated plasma was removed and stored at −80° C. untilthe assay was performed.

The substrate for the assay, Z-Lys-Phe-Arg-pNA.2HCl (Calbiochem, product# 03-32-0073) was dissolved in TBS and stored in aliquots of 1 mg/ml at−80° C. The frozen plasma samples were thawed and diluted 5 times withTBS. From the 5 times diluted plasma samples, 50 μl plasma wastransferred to a 96-well plate. In the wells containing 50 μl plasma, 50μl of 800 KIU/ml aprotinin (Calbiochem, product # 616398) was added toinhibit substrate cleavage by kallikrein. Thus, all plasma samples werediluted 40 times and had 100 μl volume. The diluted plasma samples werethen mixed 1:1 with TBS diluted substrate.

The amount of factor XIIa proteolytic activity generated duringincubation at 37° C., inducing release of the yellow-colored pNA, wasrecorded at 405 nm in 30 second time intervals for 30 minutes (MolecularDevices, Thermomax microplate-reader and SoftMax-Pro software). Resultswere expressed as mO.D./minute. A positive control was obtained byincubation of plasma with kaolin. To 1 ml of diluted (25% v/v) plasma,10 mg kaolin (Sigma, product # K-7375) was added, thoroughly shaken for10 seconds, and incubated for 5 minutes with agitation on an orbitalshaker at 37° C. After incubation, the plasma was centrifuged for 30seconds at 3,000 g. The plasma was transferred to a cleanmicrocentrifuge test tube and stored at −80° C. until factor XIIaactivity measurements were performed. The results are shown in Table 5.

TABLE 5 Factor XIIa Generation % Reduction Contact Activation (comparedSample (mOD/min) n = 3 to + control) LDPE (negative control) 0 100 Glass(positive control) 1.73 — Compound I, 7/3 0.11 93.4 Acrylamide/AMPSgraft

The results shown in Tables 3-5 indicated that the acrylamide/AMPScoatings on the LDPE disks pretreated with Compound I werehemocompatible using the in vitro evaluations previously described.

EXAMPLE 5 Surface Modification of PU by Application of Acrylamide/AMPSwith Compound II

A reagent of the structure shown as Compound II above was prepared inthe manner described in Example 1 of U.S. Pat. No. 6,278,018.

A coating solution was prepared containing 5 mg/ml of Compound II in DIwater. PU rods (5 cm, Pellethane, EG-60D, Thermedics) were cleaned withIPA (>99% purity) using a lint-free cloth and allowed to dry. The cleanrods were placed in a clear glass tube containing the Compound IIsolution. The rods were incubated in the solution at room temperaturefor approximately five minutes.

Following incubation, the substrate in the Compound II solution wasilluminated with a Dymax flood lamp (model no. 2000 EC, DymaxCorporation, Torrington, Conn.) which contained a doped mercury vaporlamp, to activate the photoreactive groups present in Compound II,thereby attaching it to the rod surface as a base coat. The rods wereilluminated for three minutes at an intensity of 1-1.5 mW/cm² in thewavelength range of 330-340 nm at the rod position. After UV curing, therods were rinsed in DI water for approximately 30 seconds prior to graftpolymerization.

Following the coating of the rods with the Compound II base coat, therods were placed in 8.0 ml of a mixture of acrylamide (0-10%, Aldrich)and AMPS (0-10% AMPS 2405 monomer, salt solution, Lubrizol) contained ina 10 ml glass syringe (Micro-mate interchangeable hypodermic syringewith leur lock, Popper and Sons, Inc.) The monomer mixture and thesubstrate were then deoxygenated using nitrogen gas bubbling up from thebottom of the syringe for 10 minutes. After 10 minutes of sparging themonomer solution with nitrogen, an EFOS TV light was placed at the topof the syringe.

The solution was illuminated with the EFOS light while nitrogen gas wasstill bubbling up through the monomer solution. The solution wasilluminated for 150 seconds at an intensity of 10 mW/cm², as measuredwith a Radiometer (International Light, IL1400A with SEL005/NS335/W), inthe 330-340 nm wavelength at a distance of 3.0 cm from the end of thelight guide. After exposing to the UV illumination, the rods wereremoved from the grafting solution and washed in DI water to remove anyunbound monomer.

Lubricity and Durability

After coating, the rods were evaluated for lubricity/durability byfriction measurements as described in Example 1. The results shown inTable 6 indicated that the coating improved the lubricity of thesubstrate over uncoated substrate. The results also indicated that thecoating remained lubricious over 15 cycles indicating a durable coating.

TABLE 6 Lubricity/Durability Testing Cycle 1 Cycle 15 % Force FrictionFriction % Increase Average of Reduction Force Force (Cycle 1 15 Cycles(compared to Substrate (grams) (grams) to 15) (grams) uncoated)Polyurethane- — — — 190.6 uncoated n = 1 Polyurethane 6.7 5.9 −12.2 5.996.9 Compound II 1 mg/ml 7% Acrylamide 3% AMPS graft n = 3 Polyurethane3.8 3.6 −5.3 3.6 98.1 Compound II 5 mg/ml 7% Acrylamide 3% AMPS graft n= 3 PEBAX - — — — 190.3 uncoated n = 2 PEBAX 11.9 17.5 47.1 14.3 92.3Compound II 1 mg/ml 7% Acrylamide 3% AMPS graft n = 3 PEBAX 7.1 8.0 12.77.5 96.1 Compound II 5 mg/ml 7% Acrylamide 3% AMPS graft n = 3Silicone - — — — 157.6 — uncoated n = 3 Silicone 21.2 20.1 −5.2 19.892.1 Compound II 1 mg/ml 7% Acrylamide 3% AMPS graft n = 3

Bacterial Adherence

Bacterial adherence experiments for the monomer grafted PU rods wereevaluated as described in Example 1. The bacterial adherence results inTable 7 indicate that the resulting graft coatings were significantlyless adherent to the three organisms tested as compared to uncoatedsurfaces.

TABLE 7 Bacterial Adherence Assay % Reduction compared to uncoatedSubstrate - coating Organism (n = 6) Polyurethane Compound II 1 mg/ml S.epidermidis 96.3 7% Acrylamide 3% AMPS graft n = 6 Polyurethane CompoundII 1 mg/ml C. albicans 97.3 7% Acrylamide 3% AMPS graft n = 6Polyurethane Compound II 1 mg/ml P. mirabilis 99.3 7% Acrylamide 3% AMPSgraft n = 6 PEBAX Compound II 1 mg/ml S. epidermidis 97.7 10% AMPS n = 6PEBAX Compound II 1 mg/ml C. albicans 99.0 7% Acrylamide 3% AMPS graft n= 6 PEBAX Compound II 1 mg/ml P. mirabilis 96.0 10% AMPS graft n = 6Silicone Compound II 1 mg/ml S. epidermidis 78.3 7% Acrylamide 3% AMPSgraft n = 6

EXAMPLE 6 Surface Modification of PEBAX by Application ofAcrylamide/AMPS with Compound II

PEBAX rods (Medical Profiles, Inc.) were coated as described in Example5. The results for lubricity/durability and bacterial adherence areshown in Table 6 and Table 7, respectively. The graft coatings on thePEBAX improved both lubricity/durability and significantly reducedbacterial adherence.

EXAMPLE 7 Surface Modification of Silicone Rubber (SR) by Application ofAcrylamide/AMPS with Compound II

Silicone rubber (SR) rods were obtained and coated as described inExample 5. The results of studies for lubricity/durability and bacterialadherence are shown in Table 6 and Table 7, respectively. The results ofthe coatings on SR again indicated improved lubricity and durabilityover uncoated material and the resulting graft coating was significantlyless adherent to the three organisms tested as compared to uncoatedsurfaces.

EXAMPLE 8 Surface Modification and Hemocompatibility Analysis of LDPECoated with Acrylamide/AMPS and Compound II

Low density polyethylene disks were precoated with Compound II and graftcoated with acrylamide/AMPS as described in Example 5. After coating,the disks were evaluated for in vitro hemocompatibility propertiesincluding platelet adhesion, fibrinogen binding, and Factor XIIageneration as previously described (Example 4). The results shown inTables 8-10 indicate that grafting with acrylamide/AMPS on polyethylenepretreated with Compound II was hemocompatible using in vitroevaluations.

TABLE 8 Platelet Adhesion % Reduction % Platelet Standard (compared toSample Coverage (n = 3) Deviation uncoated) Uncoated exp 1 62.3 3.1 —Compound II 1 mg/ml 0.3 0.3 >99 7/3 Acrylamide/AMPS graft exp 1 Uncoatedexp 2 54 10.4 — Compound II 1 mg/ml 0.06 0 >99 7/3 Acrylamide/AMPS graftexp 2

TABLE 9 Fibrinogen binding Mean ± SD % Reduction (Absorbance at(compared to Sample 650 nm) n = 3 uncoated) Uncoated 0.294 ± 0.024 —Compound II 1 mg/ml 0.095 ± 0.019 68 7/3 Acrylamide/AMPS graft

TABLE 10 Factor XIIa Generation % Reduction Contact Activation (comparedSample (mOD/min) n = 3 to + control) LDPE (negative control) 0 100 Glass(positive control) 1.73 — Compound II 1 mg/ml 7/3 0.38 78.0Acrylamide/AMPS graft

EXAMPLE 9 Surface Modification and Hemocompatibility Analysis of LDPECoated with Acrylamide/AMPS Pretreated with Compound I or Compound II

Low density polyethylene rods were precoated with Compound I or CompoundII as previously described in Example 4 and Example 8, respectively.After pretreatment, the rods were graft coated with acrylamide/AMPS asdescribed in Example 5 and evaluated for platelet adhesion and activatedcoagulation time as described below.

Evaluation of Radiolabeled Platelet Adhesion and Activated CoagulationTime

Fresh bovine blood was obtained from an abattoir and collected intocollapsible containers containing heparin. Final concentration ofheparin was 1.5 U/ml. For each experiment, 10 L blood was collected anddivided into three 3.3 L portions. The test circuit contained ⅜ inchtubing into which test rods were inserted and sealed with epoxy. Therewere 4 rods per experiment and 8 replicates. Of the 4 rods perexperiment, 3 were coated samples and 1 was an uncoated control. Therods were placed in re-circulation conduits and maintained at 37° C.Blood flow in the loop was achieved with the help of a bypass rollerpump. The flow rate was 640 ml/min, giving an average flow velocity of15 cm/s. The three test circuits were run simultaneously under identicaltest conditions. The blood circulation in the three circuits wasmaintained for 75 minutes. When the experiment was terminated, the rodswere retrieved carefully from the test circuit, examined andphotographed with a digital camera. Thrombosis on the rods wasevaluated.

To assess thrombosis, the platelets from autologous blood wereradiolabeled with ¹¹¹Indium before the initiation of the experiment.After adding 45 ml acid citrate dextrose (ACD) to 255 ml blood takenfrom the 10 L pool, the blood was centrifuged at 350 g for 15 min. Thisresulted in the sedimentation of the red cells at the bottom of thecentrifuge tubes. The supernatant, containing platelet-rich plasma (PRP)was separated from the sediment red cells into other empty centrifugetubes using a pipette. The separated PRP was then centrifuged at 850 gfor 15 min. This sedimented the platelets to the bottom of the tubes toform a pellet. After decanting the supernatant plasma which was free ofplatelets, the platelets at the bottom of the tubes were suspended bygently swirling the platelet pellets in 2 ml ACD-saline solution (5% ACD(v/v)). Radioactive label—¹¹¹Indium oxine (100 μCi)—was then added tothe suspended platelets and incubated at 37° C. for 30 minutes. Theradiolabeled platelets were then added back to the blood. Retrievedrods, after being photographed, were cut into small segments (2 to 3 cmeach) and placed in counting vials for Gamma counting.

TABLE 11 % CPM (radiolabeled platelet counts per minute) and ACT(activated coagulation time) Compound II Compound I Experiment Uncoated7/3 graft 7/3 graft ACT 1 13.78 6.05 14.22 250 2 96.48 0.51 1.75 251 388.16 4.40 3.10 237 4 62.56 8.68 12.62 309 5 52.65 11.72 11.25 296 677.93 5.45 4.32 287 7 89.57 0.19 7.70 284 8 98.89 0.23 0.51 306 Average72.50 4.65 6.93 278 Std Dev 28.73 4.23 5.27 28 Excluding Exp. 1 Average80.89 4.45 5.89 281 Std Dev 17.50 4.53 4.72 27These results indicate that both Compound I and Compound II served as asuccessful precursor to grafting with a monomer mixture of acrylamideand AMPS. The resulting coating showed a statistical improvement inhemocompatible performance over uncoated PE material.

EXAMPLE 10 Surface Modification of Silicone Rubber (SR) by Apolicationof Acrylamide or Methoxy Polyethyleneglycol (PEG) 1000Monomethylmethacrylate (MMA) with Compound III

A reagent according to the structure of Compound III was prepared in themanner described in Example 2 of U.S. Pat. No. 5,714,360.

A coating solution was prepared by dissolving Compound III at 0.5 mg/mlin DI water. A silicone contact lens was placed in a vial containing analuminum cap containing 2 ml of the Compound III coating solution. Thelens was incubated in the Compound III coating solution forapproximately 5 minutes. Following incubation, the silicone in theCompound III solution was placed under a Dymax® flood lamp with UVoutput of 1-1.5 mW/cm² (330-340 nm wavelength) at the lens position. Thesilicone remained under UV light for 1 minute. The silicone was thenremoved from the UV light, flipped, and placed back under UV light foran additional minute. The lens was rinsed and placed in DI water beforegrafting with acrylamide or PEG 1000.

Following the Compound III base coat, the silicone was placed in 8 ml of12% methoxy PEG 1000 MMA solution (in DI water) or a 10% acrylamidesolution (in DI water) contained in a 20 ml Fortuna brand syringe. Thesilicone device in the graft solution was deoxygenated using nitrogengas bubbling up from the bottom of the syringe for 10 minutes. After 10minutes of sparging with nitrogen, an EFOS UV light was placed at thetop of the syringe. While nitrogen gas was still bubbling up through thesolution, the EFOS light was turned on for 1-10 minutes. The UVintensity of the EFOS light, with a 320-390 nm filter, at the level ofthe solution was 4-6 mW/cm².

Extensive washing of the lenses under a flow of deionized (DI) water andrubbing the surface between the thumb and forefinger (approx. 30seconds) indicated a strongly adherent and lubricious layer for both thePEG and acrylamide grafted lenses. (See Table 12)

TABLE 12 Polyethyleneglycol and Acrylamide Grafted Contact LensesCoating Observation - finger rubbing Compound III 0.5 mg/ml 12% Veryslippery and durable, Methoxy PEG 1000 MMA graft little to no swellingof the silicone Compound III 0.5 mg/ml 10% Very slippery and durable,Acrylamide graft silicone material swelled.

EXAMPLE 11 Comparison of Coating Thickness Variance of PEBAX Rods GraftCoated with Compound II/Acrylamide—AMPS and PhotocrosslinkablePhotopolymers

PEBAX rods (Medical Profiles, Inc.) were graft-coated with Compound IIand acrylamide/AMPS as described in Example 6 or coated with a“PhotoLink” cocktail consisting of photopolyvinylpyrrolidone (SurModicsProduct PVO5), polyvinylpyrrolidone (Kollidon 90F, BASF),photopolyacrylamide (SurModics Product PA05), and ethylenebis(4-benzoylbenzyldimethylammonium) dibromide (SurModics Product PRO3).The coated samples, along with a sample of uncoated substrate, wereexamined by scanning electron microscopy (SEM) and atomic forcemicroscopy (AFM).

SEM analysis was conducted using a Hitachi S-800 instrument with a fieldemission electron gun. The coated rods of PEBAX were first sliced with arazor blade at a 45 degree angle to produce a sharp tip on the end ofthe rod. The tip area was then sliced at 90 degrees with LeicaUltramicrotome fitted with a diamond knife. This process reduced theshear stresses in the slicing process, and produced a flat area on thetip that contained both the coating and the substrate. After the sampleswere sputter coated with 5 nm of platinum, the microtomed area wasimaged in the SEM.

Using this process, the PhotoLink coating was readily visible, with acoating thickness of about 500 nm (0.5 μm). The result agrees with otherPhotoLink coatings, which range in thickness from 0.2 to 1 μm. However,the graft coating was not visible using this process. It was concludedthat the coating thickness of the graft coatings must fall below theresolution of the specific method described here (Hitachi S-800 electronmicroscope and ultramicrotome process). From experience, this method canimage coatings thicker than 50 to 100 nm, but cannot image coatingsthinner than 50-100 nm. Thus, a conservative estimate is that the graftcoatings were thinner than about 100 nm.

Atomic force microscopy (AFM) results corroborate the SEM results. AFManalysis of surface roughness was conducted on uncoated, graft coated,and PhotoLink coated samples using a Digital Instruments 3100 AFM. ThePEBAX rods were mounted in the AFM, and a 25 μm² area on each sample wasexamined using the “tapping mode” to avoid damaging the coatings duringanalysis.

The uncoated PEBAX rods are rough, with about a 200 nm differencebetween the highest peaks and lowest valleys. Upon coating with thegraft coating, the small-scale roughness disappears, leaving only asmoothed version of the large-scale roughness. In other words, uponcoating with the graft coating, the surface texture becomes smoother andappears as a “sand dune” type of texture. The results suggest thecoating thickness is greater than 10 nm but noticeably less than thepeak to valley measurement of 200 nm. Thus, the AFM results corroboratethe electron microscope result (coating thickness less than 100 nm).Upon coating with the PhotoLink coating, all of the roughness exhibitedby the PEBAX substrate disappeared, since the PhotoLink coatings arethicker than the roughest features of the substrate (200 nm) and thuscover up the roughness of the PEBAX surface.

Since the graft coated surfaces exhibit both lubricity andhemocompatibility, it can be assumed that the coatings are very thin,exhibiting thickness of 100 nm or less.

1. A method of forming a polymeric coating on a support surface, themethod comprising: a) providing a porous support surface; b) providing anonpolymeric grafting reagent comprising at least one photoinitatorgroup selected from the group consisting of: i) tetrakis(4-benzoylbenzylether), the tetrakis(4-benzoylbenzoate ester) of pentaerytluitol, and anacylated derivative of tetraphenylmethane, ii)4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic aciddipotassium salt (DBDS),2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic aciddipotassium salt (DBHQ), and2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-sulfonic acid mono (ordi-) sodium salt; and iii)ethylenebis(4-benzoylbenzyldimethylammonium)dibromide (Diphoto-Diquat);hexamethylenebis(4-benzoylbenzyldimethylammonium)dibromide(Diphoto-Diquat); 1,4-bis(4-benzoylbenzyl)-1,4-dimethylpiperazinediiumdibromide (Diphoto-Diquat);bis(4-benzoylbenzyl)hexamethylenetetraminediium dibromide(Diphoto-Diquat):bis[2-(4-benzoylbenzyldimethylammonio)ethyl]-4-benzoylbenzylmethylammoniumtribromide (Triphoto-Triquat): 4,4-bis(4-benzoylbenzyl)morpholiniumbromide (Diphoto-Monoquat);ethylenebis[(2-(4-benzoylbenzyldimethylammonio)ethyl)-4-benzoylbenzylmethylammonium]tetrabromide(Tetraphoto-Tetraquat); 1,1,4,4-tetrakis(4-benzoylbenzyl)piperazinediiumDibromide (Tetraphoto-Diquat); andN,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid, sodiumsalt (Diphoto-Monosulfonate), and analogues thereof; and c) providing atleast one polymerizable monomer solution adapted to be contacted withthe surface, in the presence of the grafting reagent, and to bepolymerized upon activation of the photoinitiator; and d) applying thegrafting reagent and monomer solution to the surface in a manner, andunder conditions, suitable to coat the surface with the grafting reagentand to cause the polymerization of monomers to the surface uponactivation of the grafting reagent.
 2. A method according to claim 1wherein the reagent further comprises one or more latent reactive groupsadapted to be activated in order to covalently attach the graftingreagent to the surface itself, upon activation of the latent reactivegroup(s).
 3. A method according to claim 1 wherein the method is used toform a polymeric coating on the surface of less than about 100nanometers in thickness.
 4. A method according to claim 1 wherein thesupport surface comprises a material selected from the group consistingof polyolefins, polystyrenes, poly(alkyl)methacrylates andpoly(alkyl)acrylates, polyacrylonitriles, poly(vinylacetates),poly(vinyl alcohols), chlorine-containing polymers such aspoly(vinyl)chloride, polyoxymethylenes, polycarbonates, polyamides,polyimides, polyurethanes, polyvinylidene difluoride (PVDF), phenolics,amino-epoxy resins, polyesters, silicones, polyethylene terephthalates(PET), polyglycolic acids (PGA), poly-(p-phenyleneterephthalamides),polyphosphazenes, polypropylenes, parylenes, silanes, and siliconeelastomers, as well as copolymers and combinations thereof.
 5. A methodaccording to claim 4 wherein the surface is provided by the surface of adevice selected from medical devices for use within or upon the body andbiomedical devices.
 6. A method according to claim 5 wherein the medicaldevices are selected from long-term devices selected from the groupconsisting of grafts, stents, stent/graft combinations, valves, heartassist devices, shunts, and anastomoses devices; catheters; orthopedicdevices selected from the group consisting of joint implants, fracturerepair devices, and artificial tendons; dental devices selected from thegroup consisting of dental implants and dental fracture repair devices;intraocular lenses; surgical devices selected from the group consistingof sutures and patches; synthetic prostheses; and artificial organsselected from the group consisting of artificial lung, kidney, and heartdevices and short-term devices selected from the group consisting ofvascular devices; catheters selected from the group consisting of acuteand chronic hemodialysis catheters, cooling/heating catheters, andpercutaneous transluminal coronary angioplasty (PICA) catheters; andophthalmic devices selected from the group consisting of contact lensesand glaucoma drain shunts.
 7. A method according to claim 5 wherein thebiomedical devices are selected from diagnostic slides selected from thegroup consisting of gene chips, DNA chip arrays, microarrays, proteinchips, and fluorescence in situ hybridization (FISH) slides; arrays,selected from the group consisting of cDNA arrays and oligonucleotidearrays; blood sampling and testing components; functionalizedmicrospheres; tubing and membranes; blood bags, membranes, cell culturedevices, chromatographic support materials, and biosensors.
 8. A methodaccording to claim 2 wherein the surface is provided with the polymericcoating prior to, during and/or following fabrication of the deviceitself and the photoinitiator and latent reactive groups are activatedsimultaneously to polymerize the monomers and attach the reagent to thesurface.
 9. A method according to claim 1 wherein the polymerizablemonomer is selected from: a) neutral hydrophilic monomers selected fromacrylamide, methacrylamide, N-alkylacrylamides, N-vinylpyrrolidinone,N-vinylacetamide, N-vinyl formamide, hydroxyethylacrylate,hydroxyethylmethacrylate, hydroxypropyl acrylate or methacrylate,glycerolmonomethacrylate, and glycerolmonoacrylate; b) negativelycharged hydrophilic functional monomers selected from acrylic acid,methacrylic acid, maleic acid, fumaric acid, itaconic acid, AMPS(acrylamidomethylpropane sulfonic acid), vinyl phosphoric acid,vinylbenzoic acid; and c) positively charged monomers selected from3-aminopropylmethacrylamide (APMA),methacrylamidopropyltrimethylammonium chloride (MAPTAC),N,N-dimethylaminoethylmethacrylate, N,N-diethylaminoethylacrylate, andcombinations thereof.
 10. A method according to claim 1 wherein thepolymerizable monomer comprises a macromeric polymerizable moleculeselected from poly(ethylene glycol)monomethyacrylate,methoxypoly(ethylene glycol)monomethacrylate, poly(ethyleneglycol)monoacrylate, methyacrylamidopoly(acrylamide),poly(acrylamide-co-3-methacrylamidopropylacrylamide),poly(vinylalcohol)methacrylate, poly(vinylalcohol)acrylate, andpoly(vinylalcohol)dimethacrylate.
 11. A method according to claim 1wherein the polymeric coating provides an improved combination ofproperties selected from permeability, antithrombogenicity, lubricity,hemocompatibility, wettability/hydrophilicity, durability of attachmentto the surface, biocompatibility, and reduced bacterial adhesion, ascompared to a comparable polymeric coating formed by the attachment ofpreformed polymers.
 12. A method according to claim 2 wherein thephotoinitiator(s) and latent reactive group(s) are activatedsimultaneously to polymerize the monomers and attach the reagent to thesurface,
 13. A method of forming a polymeric coating on a supportsurface, the method comprising: a) providing a porous support surface;b) providing a nonpolymeric grafting reagent comprising at least onephotoinitator group, and further comprising one or more latent reactivegroups adapted to be activated in order to covalently attach thegrafting reagent to the surface itself; wherein the grafting reagent isselected from: i) tetrakis(4-benzoylbenzyl ether), thetetrakis(4-benzoylbenzoate ester) of pentaerytluitol, and an acylatedderivative of tetraphenylmethane, ii)4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic aciddipotassium salt (DBDS),2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic aciddipotassium salt (DBHQ), and2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-sulfonic acid mono (ordi-) sodium salt; and iii)ethylenebis(4-benzoylbenzyldimethylammonium)dibromide (Diphoto-Diquat);hexamethylenebis(4-benzoylbenzyldimethylammonium)dibromide(Diphoto-Diquat); 1,4-bis(4-benzoylbenzyl)-1,4-dimethylpiperazinediiumdibromide (Diphoto-Diquat);bis(4-benzoylbenzyl)hexamethylenetetraminediium dibromide(Diphoto-Diquat):bis[2-(4-benzoylbenzyldimethylammonio)ethyl]-4-benzoylbenzylmethylammoniumtribromide (Triphoto-Triquat): 4,4-bis(4-benzoylbenzyl)morpholiniumbromide (Diphoto-Monoquat);ethylenebis[(2-(4-benzoylbenzyldimethylammonio)ethyl)-4-benzoylbenzylmethylammonium]tetrabromide(Tetraphoto-Tetraquat); 1,1,4,4-tetrakis(4-benzoylbenzyl)piperazinediiumDibromide (Tetraphoto-Diquat); andN,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid, sodiumsalt (Diphoto-Monosulfonate), and analogues thereof; c) providing atleast one polymerizable monomer solution adapted to be contacted withthe surface, in the presence of the grafting reagent, and to bepolymerized upon activation of the photo initiator; and d) applying thegrafting reagent and monomer solution to the surface in a manner, andunder conditions, suitable to coat the surface with the grafting reagentand to cause the polymerization of monomers to the surface uponactivation of the grafting reagent and the covalent attachment of thereagent to the surface.
 14. A method according to claim 13 wherein thephotoinitiator(s) and latent reactive group(s) are activatedsimultaneously to polymerize the monomers and attach the reagent to thesurface, to provide a polymeric coating on the surface of less thanabout 100 nanometers in thickness,
 15. A method according to claim 13wherein the support surface comprises a material selected from the groupconsisting of polyolefins, polystyrenes, poly(alkyl)methacrylates andpoly(alkyl)acrylates, polyacrylonitriles, poly(vinylacetates),poly(vinyl alcohols), chlorine-containing polymers such aspoly(vinyl)chloride, polyoxymethylenes, polycarbonates, polyamides,polyimides, polyurethanes, polyvinylidene difluoride (PVDF), phenolics,amino-epoxy resins, polyesters, silicones, polyethylene terephthalates(PET), polyglycolic acids (PGA), poly-(p-phenyleneterephthalamides),polyphosphazenes, polypropylenes, parylenes, silanes, and siliconeelastomers, as well as copolymers and combinations thereof, and thegrafting reagent is selected from: a) tetrakis(4-benzoylbenzyl ether),the tetrakis(4-benzoylbenzoate ester) of pentaerythritol, and anacylated derivative of tetraphenylmethane, b)4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic aciddipotassium salt (DBDS),2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic aciddipotassium salt (DBHQ), and2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-sulfonic acid mono (ordi-) sodium salt; and c) ethylenebis(4-benzoylbenzyldimethylammonium)dibromide (Diphoto-Diquat);hexamethylenebis(4-benzoylbenzyldimethylammonium) dibromide(Diphoto-Diquat); 1,4-bis(4-benzoylbenzyl)-1,4-dimethylpiperazinediiumdibromide (Diphoto-Diquat);bis(4-benzoylbenzyl)hexamethylenetetraminediium dibromide(Diphoto-Diquat):bis[2-(4-benzoylbenzyldimethylammonio)ethyl]-4-benzoylbenzylmethylammoniumtribromide (Triphoto-Triquat): 4,4-bis(4-benzoylbenzyl)morpholiniumbromide (Diphoto-Monoquat);ethylenebis[(2-(4-benzoylbenzyldimethylammonio)ethyl)-4-benzoylbenzylmethylammonium]tetrabromide(Tetraphoto-Tetraquat); 1,1,4,4-tetrakis(4-benzoylbenzyl)piperazinediiumDibromide (Tetraphoto-Diquat); andN,N-bis[2-(4-benzoylbenzyloxy)ethyl]-2-aminoethanesulfonic acid, sodiumsalt (Diphoto-Monosulfonate), and analogues thereof.
 16. A methodaccording to claim 15 wherein the surface is provided by the surface ofa device selected from medical devices for use within or upon the bodyand biomedical devices.
 17. A method according to claim 16 wherein, a)the medical devices are selected from long-term devices selected fromthe group consisting of grafts, stents, stent/graft combinations,valves, heart assist devices, shunts, and anastomoses devices;catheters; orthopedic devices selected from the group consisting ofjoint implants, fracture repair devices, and artificial tendons; dentaldevices selected from the group consisting of dental implants and dentalfracture repair devices; intraocular lenses; surgical devices selectedfrom the group consisting of sutures and patches; synthetic prostheses;and artificial organs selected from the group consisting of artificiallung, kidney, and heart devices and short-term devices selected from thegroup consisting of vascular devices; catheters selected from the groupconsisting of acute and chronic hemodialysis catheters, cooling/heatingcatheters, and percutaneous transluminal coronary angioplasty (PTCA)catheters; and ophthalmic devices selected from the group consisting ofcontact lenses and glaucoma drain shunts; and b) the biomedical devicesare selected from diagnostic slides selected from the group consistingof gene chips, DNA chip arrays, microarrays, protein chips, andfluorescence in situ hybridization (FISH) slides; arrays, selected fromthe group consisting of cDNA arrays and oligonucleotide arrays; bloodsampling and testing components; functionalized microspheres; tubing andmembranes; blood bags, membranes, cell culture devices, chromatographicsupport materials, and biosensors.
 18. A method according to claim 15wherein the polymerizable monomer is selected from: a) neutralhydrophilic structural monomers selected from acrylamide,methacrylamide, N-alkylacrylamides, N-vinylpyrrolidinone,N-vinylacetamide, N-vinyl formamide, hydroxyethylacrylate,hydroxyethylmethacrylate, hydroxypropyl acrylate or methacrylate,glycerolmonomethacrylate, and glycerolmonoacrylate; b) negativelycharged hydrophilic functional monomers selected from acrylic acid,methacrylic acid, maleic acid, fumaric acid, itaconic acid, AMPS(acrylamidomethylpropane sulfonic acid), vinyl phosphoric acid,vinylbenzoic acid; and c) positively charged monomers selected from3-aminopropylmethacrylamide (APMA),methacrylamidopropyltrimethylammonium chloride (MAPTAC),N,N-dimethylaminoethylmethacrylate, N,N-diethylaminoethylacrylate, andcombinations thereof.